The present invention relates to the compositions and methods for the inhibition of cellular proliferation. More particularly, the present invention relates to the use of antibiotics such as efrapeptins, oligomycins, mycotoxins, or mycotoxin derivatives including those comprising aurovertin B, citreoviridin, and xcex1-zearalenol structural motifs for the treatment of hyperproliferative diseases such as cancer, atherosclerosis, and psoriasis.
Cell growth is a normal process that is vital to the well-being of all living organisms. It involves two major events: the duplication of DNA and the physical division of the cell into two daughter cells (Rew, D. A., et al. Cell production rates in human tissues and tumours and their significance, Eur. J. Surg. Oncol., 26(4), 405-17 (2000)). Under physiological conditions, cell proliferation is highly regulated; in any given tissue, the fraction of dividing cells depends on the age of the organism and the properties of the tissue. For example, embryos and young animals contain a large fraction of proliferating cells. On the other hand, in adults, sustained cell growth is observed only in specific tissues, such as the intestine. The majority of adult mammalian cells are in a quiescent state.
Whether an adult mammalian cell will grow and divide or become quiescent is determined by a variety of extrinsic and intrinsic regulatory mechanisms such as the availability of space, the presence of growth-stimulatory or growth-inhibitory signals in the immediate cell environment, or the number of previous cell divisions (Fortunel, N., et al. High proliferative potential-quiescent cells: a working model to study primitive quiescent hematopoietic cells. J Cell Sci., 111,1867-75 (1998)). Disruption of these mechanisms leads to an abnormal cellular proliferation and the development of pathological conditions known as hyperproliferative diseases (Skobe, M, et al., Tumorigenic conversion of immortal human keratinocytes through stromal cell activation, Proc. Nati. Acad. Sci. USA, 95(3), 1050-5 (1998)). As used herein, the term xe2x80x9chyperproliferative diseasesxe2x80x9d refers to pathological situations characterized by aberrant cellular growth. Cancer is an example of a hyperproliferative disease. Cancer is the result of an uncontrolled cell growth due to genetic alterations that allow cells to divide indefinitely (Studzinski, G. P., et al. Oncogenes, growth, and the cell cycle: an overview. Cell Tissue Kinet. 22(6), 405-24 (1989)). On the other hand, neovascularization is the result of an abnormal endothelial cell proliferation due to the presence of excess of growth-stimulatory signals in the endothelial cell environment.
Angiogenesis or neovascularization is the formation of new blood vessels from pre-existing capillaries via a mechanism that involves degradation of the basement membrane that surrounds the parent vessel, migration of endothelial cells through the degraded membrane, proliferation of the migrating cells, endothelial cell differentiation, and loop formation (Folkman, J., Angiogenesis and angiogenesis inhibition: an overview, EXS., 79, 1-8 (1997)). With the exception of wound healing and menstruation, angiogenesis in adults is observed only in pathological situations such as cancer, atherosclerosis, and psoriasis, where it contributes to the progression and symptom manifestation of the disease (Folkman, J. Angiogenesis in cancer, vascular, rheumatoid and other disease, Nat. Med. 1(1), 27-31 (1995)). Other xe2x80x9cangiogenesis-relatedxe2x80x9d diseases include endometriosis, Kaposi""s sarcoma and other HIV-related conditions, leukemia, scleroderma, pyogenic granuloma, myocardial angiogenesis, corneal diseases, rubeosis, neovascular glaucoma, diabetic retinopathy, macular degeneration, and retrolental fibroplasia. As used herein, the term xe2x80x9cangiogenesis-related diseasesxe2x80x9d means pathological conditions that require endothelial cell proliferation for progression and symptom manifestation (Chappey, O., et al. Endothelial cells in culture: an experimental model for the study of vascular dysfunctions. Cell Biol. Toxicol., 12(4-6), 199-205 (1996)).
Increasing experimental evidence suggest that angiogenesis plays an essential role in cancer development. It has been observed that solid tumors neither grow beyond 1-2 mm3 nor metastasize unless they become vascularized (Folkman, J. What is the Evidence that Tumors are Angiogenesis Dependent?, J Natl. Canc. Inst., 82, 4-6 (1990)). Formation of tumor vasculature is necessary in order to deliver nutrients and oxygen at the tumor site, thus providing a route for tumor metastasis to distant sites. Compounds that inhibit endothelial cell proliferation have been shown to inhibit tumor neovascularization, and to prevent tumor growth and metastasis (Eatock, M. M., et al. Tumour vasculature as a target for anticancer therapy. Cancer Treat Rev. 26(3), 191-204 (2000)). Several of these inhibitors are currently under evaluation in human clinical trials (Deplanque, G., et al. Anti-angiogenic agents: clinical trial design and therapies in development, Eur. J Cancer, 36, 1713-1724 (2000)).
It is clear that therapies directed to control cellular growth, particularly endothelial cell proliferation, and most particularly angiogenesis, can have a therapeutic impact in hyperproliferative diseases, particularly those referred to as angiogenesis-related conditions. Therefore, what is needed is a composition and method, which inhibits undesirable cellular proliferation, especially the growth of blood vessels into tumors. The composition should preferably be non-toxic and produce few side effects.
In accordance with the present invention, compositions and methods are provided which are effective in inhibiting undesirable cell growth including, but not limited to, abnormal endothelial cell proliferation and tumor cell growth. The composition provided herein contains an antibiotic molecule such as efrapeptins, oligomycins, mycotoxins such as aurovertin B, citreoviridin, and xcex1-zearalenol or a mycotoxin derivative described in the general formula found below. Efrapeptins are a family of apolar, hydrophobic peptides isolated from entomopathogenic fungi. With the exception of efrapeptin A and B, efrapeptins are composed of 15 amino acids (usually common amino-acids alanine, glycine, leucine and uncommon amino-acids xcex1-aminobutyric acid, xcex2-alanine, isovaline, and pipecolic acid) with the amino-terminal acetylated and the carboxyl-terminal blocked by N-peptido-1-isobutyl-2[1-pyrrole-(1,2-xcex1)-pyrimidinium,2,3,4,5,6,7,8,-hexahydro]-ethylamine (Krasnoff, S. B., et al., Antifungal and Insecticidal Properties of the Efrapeptins: Metabolites of the Fungus Tolypocladium niveum, J Invert. Path., 58, 180-188 (1991)). Mycotoxins are secondary metabolites produced by many pathological and food spoilage fungi including Aspergillus, and Penicillium species. For example, aurovertin B is produced by Calcarisporium Arbuscula, citreoviridin is produced by Penicillium Citreoviride Biourge, while xcex1-zearalenol is produced by Fusarium (Mulheim, L. J. et al., J Chem. Soc., Chem. Commun. 874 (1974), Franck, B., et al. Citreoviridins from Aspergillus terreus, Angew Chem. Int. Ed. Engl., 19(6), 461-2 (1980), and Stipanovic, R. D., et al., Zearalenol and 8xe2x80x2-hydroxyzearalenone from Fusarium roseum, 57(2), 77-8 (1975)).
The methods provided herein for treating diseases mediated by endothelial cell proliferation involve administering to a human or animal a composition containing therapeutic dosages of efrapeptis, oligomycins, aurovertin B, citreoviridin, xcex1-zearalenol, or a derivative thereof described in the general formula found below. The method is especially useful for treating angiogenesis-related diseases such as cancer, atherosclerosis, psoriasis, diabetic retinopathy, macular degeneration, endometriosis, Kaposi""s sarcoma and other HIV-related disorders.
Accordingly, it is an object of the present invention to provide a method for treating diseases that are mediated by endothelial cell proliferation.
It is yet another object of the present invention to provide a composition for treating angiogenesis-related diseases in humans and animals.